Teicoplanin

Critical Points

Headlines

Many Gram-positive bacteria that were sensitive to simple penicillins
are now resistant. In the past, the best treatment for these
nasty bacteria was vancomycin, which unfortunately has significant
side effects. Teicoplanin is a less toxic replacement for
vancomycin in most situations where resistant organisms are
encountered.

In several clinical circumstances, empiric treatment with
teicoplanin is extremely effective. The best established of these
circumstances is neutropaenic sepsis.

Carefully selected patients may also benefit from teicoplanin
prophylaxis.

In appropriate doses, teicoplanin is usually as cost-effective
as vancomycin, with less toxicity.

In a few special circumstances, vancomycin may still be
the drug of choice, despite its extra toxicity.

The looming spectre of vancomycin (and/or teicoplanin)
resistance should encourage us to be careful and not use either drug
recklessly.

Dosing details are considered
below. The conventional dose is
6mg/kg/day (400mg/day in a 70kg adult) following one or more loading
doses, all given intravenously. The only reason for oral administration
would be Clostridium difficile-induced enterocolitis, as the drug is
very poorly absorbed orally.

Distribution

The volume of distribution is normally between 0.8 L/kg and 1.6 L/kg.
Protein binding is high (90% in serum, mainly to albumin), and good levels
(up to three times serum peak levels) are achieved in heart muscle. Penetration
into fat and cerebrospinal fluid is poor. Bone penetration of teicoplanin
is good (better than vancomycin) [ Drago L, et al. Drugs Exp Clin Res 1998;24(4):185-90 ]
The vitreous humour is poorly penetrated [ Eye 1998;12 ( Pt 2):252-5 ]

Elimination

The body doesn't metabolise teicoplanin substantially (only 3%) - it is
mainly excreted in the urine. Metabolites
have little antibacterial activity. The terminal half life is long ,
about one week (155-168 hours) and increases as renal function declines.
There are minor differences in the handling of the five main components
of teicoplanin, of no clinical significance.

With renal dysfunction:

Give the normal dose until day 4

Thereafter, if the creatinine clearance (CC) is 40 to 60ml/min,
give half the normal dose daily

or if the CC is under 40ml/min, give one third of the normal
dose, and monitor levels regularly throughout therapy.

Higher doses (12mg/kg/day) are indicated with:

Monotherapy of Staphylococcus aureus infective endocarditis
(rather add an aminoglycoside for two weeks)!

infections in intravenous drug abusers (the clearance
is greater, for reasons that are unclear)

bone and joint infections.

Drug interactions

Teicoplanin is well-tolerated when co-administered with aminoglycosides.
Nephrotoxicity with the combination is far less frequent than is the
case where equivalent doses of vancomycin are co-administered with
aminoglycosides.

Do NOT allow teicoplanin to mix with concurrently administered
ciprofloxacin lactate as precipitation occurs.

How it Works

Teicoplanin inhibits formation of cell walls in Gram-positive bacteria.
It does this by interfering with formation of links in the cell wall
(transglycosylation), acting on amino acyl-D-alanyl-D-alanine residues.
In "sensitive" organisms, it inhibits bacterial growth at levels under
8mg/Litre, killing these organisms at higher concentrations. If the
organisms are exposed to the agent for longer periods of time, then
killing occurs more effectively! In some (but possibly not all)
bacterial populations, a post-antibiotic effect has been seen,
this lasting for up to over four hours.

Mechanisms of Bacterial Resistance

Despite the increasing prevalence of glycopeptide resistance, a recent
large study still showed that most Gram-positive clinical isolates
are sensitive [ Int J Antimicrob Agents 1998 Nov;10(4):271-7 ].
Resistance to teicoplanin often implies resistance to vancomycin and
vice versa. Glycopeptide resistance has been divided into:

VanA found in Enterococcus faecalis and E faecium,
and transmitted from one enterococcus to the next by a transposon
("jumping gene") called
Tn1546,
and shows up as high-level resistance to both teicoplanin
and vancomycin.
Tn1546 is rather complex, containing several
separate genes, with complex functions and confusing names.
The gene product of "vanS" in the presence of vancomycin turns
on "vanR", which in turn stimulates production of vanA, vanX,
vanY and vanZ, as well as van H. vanH makes D-lactate, which
is then incorporated into the cell wall in place of D-alanine,
preventing the action of glycopeptides. Even more cunningly,
the vanX and vanY genes prevent normal incorporation of
D-alanine into the cell wall (otherwise the glycopeptides
could still act)! vanZ appears to mediate teicoplanin resistance,
but we're not sure how. There is evidence that vanH,A and X are
present in the organisms that produce glycopeptides - resistance
mechanisms may have originally come from them!!
[ Antimicrob Agents Chemother 1998 Sep;42(9):2215-20 ]

Inducible VanB resistance, with resistance to vancomycin but
full susceptibility to teicoplanin! The mechanism is distinct from
vanA resistance. Some vanB variants may even be dependent on
the presence of vancomycin for growth, although removal of the drug
may be not result in cure! [ Antimicrob Agents Chemother 1999 Jan;43(1):41-7 ]

Built in (constitutive) resistance to vancomycin but not
teicoplanin, found in E gallinarium and E casseliflavus, termed VanC.
VanC has been subtyped into C1..C3.

VanD has also been described.

Resistance to teicoplanin with susceptibility to vancomycin,
seen in some strains of Staphylococcus epidermidis and S. haemolyticus.

It is thought by some that administration of the drug avoparcin
to livestock and birds as an antibiotic growth promoter is one reason for the rise
in antimicrobial resistance in Enterococci. A recent article
from the
New England Journal of Medicine
supports this, finding glycopeptide
resistance commonly present in turkeys given avoparcin. Avoparcin acts
at the same site as teicoplanin and vancomycin, and has been temporarily
banned in Europe because of these suspicions. See a recent article
in the
New Scientist.

Of extreme concern is the recent emergence of decreased sensitivity
of Staphylococcus aureus to vancomycin. This resistance is not related
to the VanA..VanC genes, but we continue to worry that S aureus might
just acquire for example the VanA gene. Amazingly enough, scientists have
been rash (mad?) enough to experimentally transfer VanA into S. aureus!

There are several investigational drugs that may eventually become
clinically useful with teicoplanin resistance, however these are
not yet available. They include streptogramins (quinupristin/dalfopristin),
some fluoroquinolones (clinafloxacin, grepafloxacin, moxifloxacin,
gatifloxacin, and trovafloxacin) as well as everninomicin derivatives
(SCH27899), ketolides, and oxazolidinones (linezolid),
[ Jones RN et al, Diagn Microbiol Infect Dis 1999 Feb;33(2):101-12 ],
and possibly the glycopeptide LY333328.

A Comparison with Vancomycin

Relatively few studies have compared clinical efficacy of vancomycin
with that of teicoplanin. The following general conclusions appear
to hold:

Pittet and Harding [ J Infect 1998 Sep;37(2):127-35 ]have recently
reviewed the use of the two agents in infective endocarditis, emphasizing
that there are no randomised controlled trials comparing them in
this situation. Outcome is similar using either drug.

Teicoplanin in combination

Synergy may occur with:

Imipenem

aminoglycosides

Some penicillins

For treatment of infective endocarditis caused by Staphylococcus aureus,
the addition of an aminoglycoside is highly recommended.

References

Brogden RN & Peters DH. Drugs 1994 47:823-54. A reappraisal,
with updates on use and pharmacokinetics.

Disclaimer

Information on this page is provided for teaching purposes. You should not
make a clinical treatment decision based on information contained in this
page without consulting other references including the package insert of
the drug, textbooks and where relevant, expert opinion. We cannot be held
responsible for any errors you make in administering drugs mentioned on
this page, nor for use of any erroneous information contained on this page.